CN114269806A

CN114269806A - Degradable polyether

Info

Publication number: CN114269806A
Application number: CN201980075410.3A
Authority: CN
Inventors: 冯晓双; J·瓦格塞; Y·加努; N·哈吉克里斯蒂斯; 贾明辰; D·奥古斯丁
Original assignee: King Abdullah University of Science and Technology KAUST
Current assignee: King Abdullah University of Science and Technology KAUST
Priority date: 2018-09-17
Filing date: 2019-09-17
Publication date: 2022-04-01
Also published as: US20220033556A1; US20210309801A1; EP3853289A1; WO2020058852A1

Abstract

Embodiments of the present invention include degradable polyethers comprising ester units derived from cyclic esters or carbonate units derived from carbon dioxide, these units being incorporated into the polyethylene oxide backbone or the multifunctional core of the degradable star polyether. Embodiments include a method of forming a degradable polyether comprising contacting an ethylene oxide monomer with a lactide monomer or carbon dioxide in the presence of an alkylborane and an initiator. Embodiments include a method of forming the degradable star polyether, comprising contacting a diepoxide monomer with carbon dioxide and/or a cyclic ester in the presence of an initiator and a first amount of an alkyl borane to form a multifunctional core comprising degradable carbonate linkages and/or degradable ester linkages, and contacting the multifunctional core with an ethylene oxide monomer in the presence of a second amount of an alkyl borane to form arms of a polyether attached to the degradable multifunctional core.

Description

Degradable polyether

Background

Polyethylene oxide (PEO), commonly referred to as polyethylene glycol, is an FDA-approved polymer for clinical use due to its unique properties such as its chemical stability, its hydrophilicity, its biocompatibility, especially its non-recognition by the immune system (stealth effect), etc. The presence of a functional group at the chain end allows the biologically active molecule to bind to PEO (pegylation). Thus, so-called pegylated cargo (cargos) can be delivered to the target site without being recognized by the immune system. To prolong circulation time and improve steric shielding effect, the hydrodynamic size of the conjugate after pegylation should exceed 6-8 nm (which is the threshold for glomerular filtration) to avoid its clearance by the kidney. However, due to the recalcitrance of PEO and its potential in vivo bioaccumulation, the molar mass of PEO used should not exceed 40 kg/mol.

To overcome this problem, much effort has been devoted to imparting degradability to the PEO chains by incorporating degradable linkages into the PEO backbone. The most common strategy is via polycondensation of PEO telechelics, which involves the incorporation of ester, disulfide, acetal, oxime, imine or carbonate linkages into a PEO polycondensate. However, the PEO derivatives produced using the latter method show very broad polydispersity and undefined structure.

One typical strategy involves anionic copolymerization of ethylene oxide with other monomers and then introducing degradable linkages into the interior of the PEO backbone. For example, copolymerized ethylene oxide can be subjected to an efficient elimination reaction with epichlorohydrin to generate degradable Methylene Ethylene Oxide (MEO) repeat units within the PEO backbone. Similarly, ethylene oxide can be copolymerized with 3, 4-epoxy-1-butene (EPB) using Anionic Ring Opening Polymerization (AROP), and then the allyl portion of the EPB can be isomerized to pH-cleavable vinyl ethers. An alternative strategy involves post-oxidation treatment of the prepared PEO or commercially available PEO to generate hydrolyzable bonds along its backbone. For example, hemiacetals can be randomly incorporated into the backbone of PEO via the Fenton reaction (Fenton reaction) at neutral pH with hydrogen peroxide and ferric chloride. Acids that produce PEG have also been reported to cleave the ruthenium catalyzed post polymerization oxidative functionalization reaction of ethylene glycol-glycolic acid copolymers. Although the last two approaches provide a well-defined structure and narrow polydispersity for degradable polyethylene glycols, they suffer from the following drawbacks: the synthesis requires many steps and the problem of compatibility with functional groups should be solved during post-polymerization steps.

Polylactic acid (PLLA) is another important polymer, which is widely used in the biomedical field due to its biocompatibility and degradability as well as availability from biological resources. However, PLLA has biomedical applications different from PEO due to its high crystallinity, hydrophobicity and degradability. Copolymerizing LLA with other monomers represents a general strategy to tailor its physical properties to various biomedical applications. For example, diblock copolymers or triblock copolymers have been obtained by sequential polymerization of various monomers with LLA. With respect to epoxide monomers (i.e., ethylene oxide), only a limited number of studies have been reported in the literature describing copolymers of epoxide monomers with LLA. One report mentions: in addition to seeking to increase the PLLA block from the PEO macroinitiator, various aluminum (Al) and tin-aluminum (Sn-Al) bimetallic catalysts were used to prepare LLA-EO multi-block copolymers that showed broad distribution. Another report is the use of a typical Vandenberg catalyst to obtain random copolymers of LLA and EO of high molar mass. In each of these reports, the theoretical focus was to investigate the "copolymerizability" of LLA with epoxides using various coordination catalysts, and to characterize the type of copolymer ultimately obtained: a multi-block copolymer in the first case and a random copolymer in the second case.

Disclosure of Invention

In general, embodiments of the invention describe degradable polyethers, and methods of forming degradable polyethers, degradable polyethers combined with bioactive molecules, and the like.

Embodiments of the present invention describe degradable polyethers comprising ester units derived from cyclic esters (e.g., lactide) or carbonate units derived from carbon dioxide and incorporating these units into a polyethylene oxide backbone or polyfunctional polycarbonate core of a star-shaped polyethylene oxide.

Embodiments of the present invention describe methods of forming degradable polyethers comprising contacting an ethylene oxide monomer with a cyclic ester or carbon dioxide in the presence of an alkylborane and an initiator.

Embodiments of the present invention describe modified biomolecules comprising a bioactive molecule combined with a degradable polyether having ester units or carbonate units incorporated into a polyethylene oxide backbone.

Embodiments of the present invention describe a method of forming a degradable star polyether comprising contacting a diepoxide monomer with carbon dioxide and/or a cyclic ester in the presence of an initiator and a first amount of an alkyl borane to form a multifunctional core containing degradable carbonate linkages and/or degradable ester linkages, and contacting the multifunctional core with an ethylene oxide monomer in the presence of a second amount of an alkyl borane to form arms of a polyether attached to the degradable multifunctional core.

The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Drawings

This written disclosure describes non-limiting and non-exhaustive illustrative embodiments. In the drawings, which are not necessarily to scale, like reference numerals depict substantially similar components throughout the views, and similar reference numerals with different letter suffixes represent substantially similar components. These drawings are generally by way of example, but are not intended to limit the various embodiments discussed in the illustrative document.

Reference is made to the exemplary embodiments depicted in the accompanying drawings, in which:

fig. 1 is a flow diagram of a method of forming a degradable copolymer according to one or more embodiments of the present disclosure;

FIG. 2 is a schematic illustration of a reaction scheme for forming a degradable copolymer according to one or more embodiments of the present disclosure;

fig. 3 is a flow diagram of a method of forming a degradable star polyether according to one or more embodiments of the present disclosure;

FIG. 4 is a representative illustration of a poly (EO-co-LLA) (P (EO-co-LLA)) random copolymer (item 7 of Table 1) according to one or more embodiments of the present disclosure¹H NMR spectrum;

fig. 5 is a graph of GPC traces of various copolymer samples targeted at 100DP to 500DP (table 1), according to one or more embodiments of the present disclosure;

FIG. 6 is an infrared spectrum showing azide-incorporated copolymers according to one or more embodiments of the present disclosure (item 21 of Table 1);

FIG. 7 is P in toluene according to one or more embodiments of the present disclosure₄Graphical representation of copolymerization reactivity ratio (reactivity ratio) plot of/PMBA (

entries

1,2,3 of Table 2);

FIG. 8 is a graphical representation of a plot of copolymerization reactivity ratios of TBACl in toluene (

entries

4, 5,6 of Table 2) according to one or more embodiments of the present disclosure;

FIG. 9 is a graphical representation of a plot of copolymerization reactivity ratios of PPNCl in benzene according to one or more embodiments of the present disclosure (

entries

7,8, 9 of Table 2);

FIG. 10 is a graphical representation of DSC profiles of poly (EO-co-LLA) copolymers having different ester compositions in accordance with one or more embodiments of the present disclosure;

fig. 11 is a graphical representation of GPC profiles of capped poly (EO-co-LLA) copolymers before and after degradation according to one or more embodiments of the present disclosure (item 12 of table 1);

FIG. 12 shows a reaction scheme illustrating the synthesis of a PEO star-like homopolymer (PVDOX-EO) according to one or more embodiments of the present disclosure;

FIG. 13 shows item 21 of Table 4 in accordance with one or more embodiments of the present disclosure¹H NMR characterization;

figure 14 shows GPC graphs of item 21 of table 4 in accordance with one or more embodiments of the present disclosure;

FIG. 15 shows item 22 of Table 4 in accordance with one or more embodiments of the present disclosure¹H NMR characterization;

figure 16 shows GPC graphs of item 22 of table 4 in accordance with one or more embodiments of the present disclosure;

FIG. 17 illustrates item 23 of Table 4 in accordance with one or more embodiments of the present disclosure¹H NMR characterization;

figure 18 shows a GPC diagram of item 23 of table 4 in accordance with one or more embodiments of the present disclosure;

FIG. 19 shows item 24 of Table 4 in accordance with one or more embodiments of the present disclosure¹H NMR characterization;

figure 20 shows a GPC diagram of item 24 of table 4 in accordance with one or more embodiments of the present disclosure;

FIG. 21 shows item 25 of Table 4 in accordance with one or more embodiments of the present disclosure¹H NMR characterization;

figure 22 shows a GPC diagram of item 25 of table 4 in accordance with one or more embodiments of the present disclosure;

FIG. 23 shows item 26 of Table 4 in accordance with one or more embodiments of the present disclosure¹H NMR characterization;

figure 24 shows a GPC diagram of item 26 of table 4 in accordance with one or more embodiments of the present disclosure;

figure 25 shows a GPC diagram of item 27 of table 5 in accordance with one or more embodiments of the present disclosure;

figure 26 shows a GPC diagram of item 28 of table 5 in accordance with one or more embodiments of the present disclosure;

figure 27 shows a GPC diagram of item 30 of table 5 in accordance with one or more embodiments of the present disclosure;

figure 28 shows a GPC diagram of item 33 of table 5 in accordance with one or more embodiments of the present disclosure;

FIG. 29 shows item 33 of Table 5 in accordance with one or more embodiments of the present disclosure¹And H NMR characterization.

Detailed Description

The present invention relates to methods of forming degradable polyethers, and the like. These degradable polyethers can include a controllable and adjustable content of degradable ester linkages (e.g., ester units) or degradable carbonate linkages (e.g., carbonate units) incorporated into the polyether backbone or multifunctional core of the star polyether. For example, embodiments include degradable polyethers prepared as random copolymers comprising ester units derived from cyclic esters (e.g., L-lactide) and/or carbonate units derived from carbon dioxide, which units are randomly incorporated into the polyether backbone. Embodiments also include degradable polyethers prepared as star polymers, the polyethers including arms attached to polyethers having multifunctional cores containing carbonate units or ester units. The methods disclosed herein provide a means to quantify and/or chain length of ester units and carbonate units incorporated into the degradable polyether. For example, in one embodiment, the degradable polyether may comprise about 5% ester units incorporated into the polyether backbone, wherein each ester unit has an average length of about two adjacent ester groups or less. By incorporating degradable linkages into the polymer backbone in this manner, degradability can be imparted to the polyether without altering the inherent properties of the polymer.

The degradable polyethers of the present disclosure can be prepared directly by anionic ring-opening copolymerization of ethylene oxide monomers with cyclic esters or carbon dioxide. Anionic copolymerization may be carried out in the presence of an activator (i.e., an alkylborane) and an initiator. The presence of the activator can selectively increase the reactivity of the ethylene oxide monomer and inhibit transesterification and/or the formation of cyclic carbonates. For example, under stoichiometric conditions, the activator and initiator may react to form an acid complex. The acid radical type complex can be used for initiating anionic copolymerization reaction. In some embodiments, where the addition of the acid-based complex fails to provide sufficient nucleophilicity to deactivate the ethylene oxide monomer, in such cases, it may be desirable to add a stoichiometric excess of activator to initiator to ensure activation of the ethylene oxide monomer. By treating in this way, the content of degradable bonds can be precisely controlled, thereby giving the degradable ether a definite structure and a controllable molar mass, and obtaining a low polydispersity. Furthermore, the process is versatile and can be used for the synthesis of functionalized linear and/or branched polyethylene oxides, and star degradable polyethylene oxides, etc.

In some embodiments, these degradable polyethers can be further prepared as difunctional or heterobifunctional polyethers for modification of biomolecules. For example, these degradable polyethers can be formed so as to have a plurality of functional groups at their ends that allow the binding of bioactive molecules to polyethylene oxide through a process commonly referred to as pegylation. Thus, embodiments of the present disclosure further describe modified biomolecules comprising a bioactive molecule bound to the degradable polyether of the present disclosure. Thus, bioactive molecules such as peptides, proteins, and enzymes can be modified by covalent attachment to degradable polyethers.

Definition of

The definitions of the terms set forth below are as follows. Other terms and phrases in this disclosure should be construed according to their ordinary meaning as understood by those skilled in the art.

The term "degradable polyether" as used herein refers to any polyether that contains degradable linkages. For example, these degradable linkages may occur in the polymer backbone, or in groups between the polymer backbone and one or more terminal functional groups of the polymer, or within the multifunctional core of the star polymer, among other locations. In the context of star polymers, degradable star polyethers can include polyether star polymers or heterotypic star polymers having a multifunctional core that includes degradable linkages.

The term "degradable linkage" as used herein refers to any unit or segment of a polymer that is capable of being degraded. The term "degradable linkage" includes ester units and carbonate units. Thus, herein, the terms "ester unit" and "degradable ester linkage", as well as "carbonate unit" and "degradable carbonate linkage", and the like, are used interchangeably. The degradation mechanism of these chemical bonds may depend on the intended application. For example, these degradable bonds may be hydrolytic bonds, enzymatic bonds, pH-degrading bonds, acid-degrading bonds, and the like.

The term "cyclic ester" as used herein includes mono-esters, cyclic di-esters, cyclic tri-esters, and the like. One non-limiting example of a cyclic ester is lactide. The term "lactide" as used herein may refer to one or more of the three stereoisomeric forms of lactide. The three stereoisomeric forms of lactide include L-lactide, D-lactide, and meso-lactide.

The term "ester unit" as used herein refers to any segment of a polymer comprising at least one ester group. The polymer may comprise a plurality of ester units. Each ester unit may comprise one or more adjacent ester groups. In general, the formula (-RC (═ O) OR')_a) To indicate an ester group, wherein a is at least 1, and R' are conventional, without particular limitation, depending on from which monomer the ester group is derived. For example, the ester unit may comprise one or more adjacent lactides. The ester units of the polymer can be described by the average length, whereThe average length of an ester unit may refer to the average number of adjacent ester groups present in the polymer.

The term "carbonate unit" as used herein refers to any segment of a polymer comprising at least one carbonate group. The polymer may comprise a plurality of carbonate units. Each carbonate unit may comprise one or more adjacent carbonate groups. In general, the formula (-ROC) (═ O) OR' -)_aTo indicate a carbonate group, wherein a is at least 1, is not particularly limited, but depends on from which monomer the carbonate group is derived. For example, the carbonate unit may comprise one or more adjacent monoethyl carbonates. Carbonate units in a polymer may be described by an average length, where the average length of a carbonate unit may refer to the average number of adjacent carbonate groups present in the polymer.

The term "aliphatic" or "aliphatic group" as used herein refers to a hydrocarbon moiety, wherein the hydrocarbon moiety may be linear (e.g., unbranched or linear), branched, or cyclic, and/or may be fully saturated, or contain one or more units of unsaturation, but is not aromatic. The term "unsaturated" refers to a moiety having one or more double and/or triple bonds. Thus, the term "aliphatic" includes alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkynyl groups, as well as combinations thereof. The aliphatic group may contain 30 carbon atoms or less, or any number of carbon atoms in the range of 1 to 30, or any incremental number of carbon atoms in the range of 1 to 30. Non-limiting examples of aliphatic groups include linear or branched alkyl, alkenyl, and alkynyl groups, and mixtures thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl, and (cycloalkyl) alkenyl.

The term "alkyl" as used herein refers to a saturated, straight or branched chain hydrocarbon radical in which hydrogen atoms have been removed from aliphatic moieties. The alkyl group may optionally include straight or branched chains having 1 to 20 carbon atoms. Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, sec-pentyl, isopentyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-ethylbutyl, 1-methylbutyl, 2-methylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, and the like.

The term "alkenyl" as used herein refers to a group derived from a straight or branched aliphatic moiety having at least one carbon-carbon double bond from which a hydrogen atom has been removed. The term "alkynyl" as used herein refers to a group derived from a straight or branched aliphatic moiety containing at least one carbon-carbon triple bond from which a hydrogen atom has been removed. Non-limiting examples of alkenyl groups include: vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, allyl, 1, 3-butadienyl and allenyl. Non-limiting examples of alkynyl groups include: ethynyl, 2-propynyl and 1-propynyl. When "alkene" refers to a compound H-R or a moiety H-R, where R is alkenyl.

The term "alicyclic", "carbocycle" or "carbocyclic" as used herein refers to a saturated or partially unsaturated cyclic aliphatic monocyclic or polycyclic (including fused, bridged and spiro-fused) ring system having 3 to 20 carbon atoms. Alicyclic groups can optionally contain 3 to 15 carbon atoms, optionally 3 to 12, optionally 3 to 10, optionally 3 to 8, and/or optionally 3 to 6 carbon atoms. The terms "alicyclic," "carbocyclic," or "carbocyclic" also include aliphatic rings fused to one or more aromatic or non-aromatic rings, such as a tetralin ring, where the point of attachment is on the aliphatic ring. Carbocyclyl groups may be polycyclic, for example bicyclic or tricyclic. It is to be understood that an alicyclic group may contain one or more alkyl substituents, attached or unattachedAlicyclic rings, e.g. -CH₂-cyclohexyl. Non-limiting examples of carbocycles include: cyclopropane, cyclobutane, cyclopentane, cyclohexane, bicyclo [2,2,1 ]]Heptane, norbornene, phenyl, cyclohexene, naphthalene, spiro [4.5 ]]Decane, cycloheptane, adamantane and cyclooctane.

The term "heteroaliphatic" (including heteroalkyl, heteroalkenyl, and heteroalkynyl) as used herein refers to an aliphatic group, as defined above, which additionally contains one or more heteroatoms. The heteroaliphatic group can optionally contain 2 to 21 atoms, optionally 2 to 16, optionally 2 to 13, optionally 2 to 11, optionally 2 to 9, and/or optionally 2 to 7 atoms, wherein at least one atom is a carbon atom. Non-limiting examples of heteroatoms include O, S, N, P and Si. In the case where the heteroaliphatic group has two or more heteroatoms, these heteroatoms may be the same or different. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include saturated or partially unsaturated groups.

The term "alicyclic group" as used herein refers to a saturated or partially unsaturated cyclic aliphatic monocyclic or polycyclic (including fused, bridged and spiro-fused) ring system having 3 to 20 carbon atoms. The cycloaliphatic group can optionally have 3 to 15 carbon atoms, alternatively 3 to 12, alternatively 3 to 10, alternatively 3 to 8, and/or alternatively 3 to 6 carbon atoms. The term "alicyclic" includes cycloalkyl, cycloalkenyl and cycloalkynyl. It is understood that an alicyclic group can comprise an alicyclic ring with one or more alkyl substituents, either attached or unattached, such as-CH₂-cyclohexyl. Specifically, C_3-20Examples of cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and cyclooctyl.

The term "heteroalicyclic" as used herein refers to an alicyclic group as defined above which has one or more ring heteroatoms in addition to carbon atoms, which heteroatoms may optionally be selected from O, S, N, P and Si. Heteroalicyclic groups may optionally contain 1 to 4 heteroatoms, wherein the heteroatoms may be the same or different. Heteroalicyclic groups may optionally contain 5 to 20 atoms, preferably 5 to 14, and/or optionally 5 to 12 atoms.

The term "aryl", "aryl" or "aryl ring" as used herein refers to a monocyclic or polycyclic ring system having 5 to 20 carbon atoms, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 12 ring members. The term "aryl" may be used alone or as part of a larger group such as "aralkyl", "aralkoxy", or "aryloxyalkyl". Non-limiting examples of aryl groups include: phenyl, methylphenyl, (dimethyl) phenyl, ethylphenyl, biphenyl, indenyl, anthracenyl, naphthyl, azulenyl, or the like. The term "aryl" includes fused rings such as indanes, benzofurans, phthalimides, phenanthridines, and tetrahydronaphthalenes. When "arene" refers to the compound H-R, where R is aryl.

The term "heteroaryl", as used herein, whether used alone or as part of another term (such as "heteroaralkyl" or "heteroaralkoxy"), refers to a monocyclic or polycyclic group of 5 to 14 ring atoms and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes nitrogen or sulfur in any oxidation state, as well as any quaternized form of nitrogen. The term "heteroaryl" also includes groups in which a heteroaryl ring is fused to one or more aryl, alicyclic, or heterocyclic rings, where the linking group or point of attachment is on the heteroaromatic ring. Non-limiting examples of heteroaryl groups include: indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, furanyl, imidazolyl, indolyl, indazolyl, methylpyridinyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, triazinyl, and pyrido [2,3-b ] -1, 4-oxazin-3 (4H) -one.

The term "aralkyl" as used herein refers to an alkyl group as defined previously wherein one of the hydrogen atoms is substituted with an aryl and/or heteroaryl group, thereby forming a heteroaralkyl group wherein the alkyl, aryl and/or heteroaryl portions are independently substituted. The term "nitrogen" when used in reference to a ring atom of a heterocyclic ring includes substituted nitrogens. Non-limiting examples of aralkyl groups are benzyl (benzyl, Bn) and 2-phenylethyl.

Non-limiting examples of alicyclic, heteroalicyclic, aryl and heteroaryl groups include, but are not limited to: cyclohexyl, phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazole, dithiacene, furan, imidazole, imidazoline, imidazolidinyl, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, naphthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, tetrahydropyrrole, pyrroline, quinoline, quinoxaline, quinazoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiadiazoline, and the like, Thianaphthalenes, thiopyrans, triazines, triazoles and trithianes.

As used herein, the terms "halide," "halo," and "halogen" are used interchangeably and refer to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like, optionally a fluorine atom, a bromine atom, or a chlorine atom, and optionally a fluorine atom. The term "haloalkyl" includes fluorinated or chlorinated groups, including perfluorinated compounds. Non-limiting examples of haloalkyl groups include: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloromethyl, bromomethyl, iodomethyl, and the like.

The term "alkaryl" as used herein, means an aryl and/or heteroaryl group, as defined above, in which one or more hydrogen atoms are replaced by an alkyl and/or heteroalkyl group, as defined above.

The term "alkoxy" as used herein refers to the group-OR, wherein R is alkyl and/OR heteroalkyl, as defined herein. Non-limiting examples of alkoxy groups include: -OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-OCH(CH₂)₂、-OC₃H₆、-OC₄H₈、-OC₅H₁₀、-OC₆H₁₂、-OCH₂C₃H₆、-OCH₂C₄H₈、-OCH₂C₅H₁₀、-OCH₂C6H₁₂And the like. Non-limiting examples of alkoxy groups also include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, sec-pentoxy, n-hexoxy, isohexoxy, n-heptoxy, n-octoxy, n-nonoxy, n-decoxy, n-undecyloxy, n-dodecoxy, n-tridecoxy, n-tetradecoxy, n-pentadecoxy, n-hexadecyloxy, n-heptaalkoxy, n-octadecyl, n-nonadecyl oxy, n-eicosoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-methylbutoxy, 1-ethyl-2-methylpropoxy, 1, 2-trimethylpropoxy, 1-dimethylbutoxy, 1, 2-dimethylbutoxy, n-pentoxy, isopentoxy, n-pentoxy, n-heptoxy, n-octoxy, n-dodecoxy, n-eicosoxy, 1-dimethylpropoxy, 1, 2-dimethylbutoxy, 2, n-propoxy, 2-dimethylpropoxy, 2, and the like, 2, 2-dimethylbutyloxy, 2, 3-dimethylbutyloxy, 1, 3-dimethylbutyloxy, 2-ethylbutoxy, 2-methylpentyloxy, 3-methylpentyloxy, and the like.

The terms "alkenyloxy", "alkynyloxy", "aryloxy", "aralkoxy", "heteroaryloxy", and "acyloxy", as used herein, refer to a group defined as-OR, wherein R represents alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and acyl, respectively. Examples include, but are not limited to, aryloxy (such as-O-Ph) and aralkoxy (such as-OCH)₂-Ph (-OBn) and-OCH₂CH₂-Ph)。

The term "optionally substituted" as used herein means that one or more hydrogen atoms in the optionally substituted moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when more than one position may be substituted with more than one substituent selected from a particular group in any given structure, the substituents at each position may be the same or different. Combinations of substituents contemplated by the present invention are optionally those substituents that form stable compounds. Non-limiting examples of substituents useful in the present invention include: halogen, hydroxy, nitro, carboxylate, carbonate, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, alkylaryl, amino, amido, imine, nitrile, silyl ether, ester, sulfoxide, sulfonyl, acetylide, phosphonite, sulfonate, or optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl, or heteroaryl (e.g., optionally substituted with halogen, hydroxy, nitro, carbonate, alkoxy, aryloxy, alkylthio, arylthio, amino, imine, nitrile, silyl, sulfoxide, sulfonyl, phosphonite, sulfonate, or acetylide), and the like.

Embodiments of the present invention describe degradable polyethers and controllable and adjustable levels of degradable linkages incorporated therein. In some embodiments, the degradable polyether is prepared as a random copolymer in which ester units or carbonate units are randomly incorporated into the polyether backbone. For example, these degradable polyethers may comprise ester units derived from cyclic esters (such as lactide) or carbonate units derived from carbon dioxide, and these units are randomly incorporated into the polyethylene oxide backbone. Non-limiting examples of such degradable polyethers include ethylene oxide-lactide copolymer (poly (ethylene oxide-co-lactide)), ethylene oxide-ethyl carbonate copolymer, and the like. These degradable polyethers can also be prepared as difunctional or heterobifunctional copolymers, wherein the ends of these degradable polyethers can have multifunctional groups suitable for bio-conjugation and applications. In other embodiments, these degradable polyethers are prepared as star polymers in which carbonate units or ester units are incorporated into multifunctional cores having polyether arms attached thereto. Non-limiting examples of such degradable polyethers include polyethylene oxide star polymers that are linked to a degradable polycarbonate core.

In some embodiments, the polymer backbone comprises polyethylene oxide. For example, the polymer backbone may be a polyethylene oxide backbone, which may be linear or branched, substituted or unsubstituted, and functionalized or unfunctionalized. In one embodiment, the polyethylene oxide backbone may be represented generally by the following formula:

(-CR₂-CR₂-O-)_n

wherein each R is independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, alkenyl, heteroalkenyl, cycloalkene, alkynyl, heteroalkynyl, cycloalkynyl, alkoxy, aryl, heteroaryl, aralkyl, alkylene, alkaryl, alkarylene, halogen, or combinations thereof, each of which groups may be substituted or unsubstituted, functional or nonfunctional; wherein n is at least 1. In one embodiment, the polyethylene oxide backbone is a functionalized linear polyethylene oxide. In another embodiment, the polyethylene oxide backbone is a functionalized branched polyethylene oxide.

Ester units derived from cyclic esters or carbonate units derived from carbon dioxide can be incorporated (e.g., randomly incorporated) into the polyethylene oxide backbone or into the multifunctional core of a degradable polyether (e.g., polyethylene oxide star polymer). The term "ester unit" as used herein refers to any segment of the copolymer that contains at least one ester group (e.g., -RC (═ O) OR' -). For example, in one embodiment, the ester units may comprise one or more adjacent lactide units (e.g., L-lactide units), wherein the lactide units are represented by the chemical structure:

the term "carbonate unit" refers to any segment of a copolymer comprising at least one carbonate group (e.g., -ROC (═ O) OR' -). For example, in one embodiment, a carbonate unit may comprise one or more adjacent monoethyl carbonate units, wherein the monoethyl carbonate unit is represented by the following chemical structure:

in one embodiment, the degradable polyether may be represented by the following chemical structure:

wherein m is<n or m<<n; wherein X is selected from Cl, Br, N₃、OH、O-、CH₂＝CHCH₂O-, or a combination thereof. In one embodiment, the degradable polyether may be represented by the following chemical structure:

wherein m is<n or m<<n; wherein X is selected from Cl, Br, N₃、OH、O-、CH₂＝CHCH₂O-, or a combination thereof. In one embodiment, the inner core of the degradable polyether may be represented by the following chemical structure:

these are provided by way of example and therefore should not be limiting as other degradable polyethers are also within the scope of the present invention.

The content of ester units and carbonate units incorporated into the copolymer and multifunctional core is highly tunable, allowing control over the properties and characterization of the degradable polyether product formed. For example, the polyethylene oxide backbone may be incorporated with a very low to moderate content of ester units or carbonate units sufficient to impart degradability to the copolymer, or in the case of some star polymers, moderate to high levels of ester units and/or carbonate units may be present in the multifunctional core. In some embodiments, ester units and/or carbonate units may be incorporated without altering or maintaining the inherent properties of either monomer. In one embodiment, the content of ester units and/or carbonate units is very low, for example from about 3% to about 5%. In other embodiments, the ester content and/or carbonate content of the degradable polyether may be about 20% or less. For example, the ester content and/or carbonate content may be about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.1% or less, or any incremental value thereof. In other embodiments, such as in the case of star polymers, the ester content and/or carbonate content may be at least about 70% or more. For example, the ester content and/or carbonate content may be about 85%, about 88%, about 89%, or about 90%, or any value or range between 70% and 100%.

The average length of the ester units and carbonate units incorporated into the copolymer and/or the multifunctional core can also be adjusted. The average length of the ester units may refer to the average number of adjacent carbonate groups present along the copolymer backbone and/or in the multifunctional core within each ester unit. The average length of the carbonate units may refer to the average number of consecutive carbonate groups present along the copolymer backbone and/or present in the multifunctional core within each carbonate unit. These units may be determined in terms of groups, such as ester and/or carbonate groups, or may be determined in terms of monomers, such as lactide and/or carbonate monomers. For example, in one embodiment, the average lengths of the ester units and carbonate units present along the copolymer backbone may be about two lactide groups or less and two monoethylene carbonate groups or less, respectively. In other embodiments, the average length of the ester units and carbonate units present along the copolymer backbone may be about 10 or less. For example, the average length of the ester units and carbonate units may be about 10 or less, about 9 or less, about 8 or less, about 7 or less, about 6 or less, about 5 or less, about 4 or less, about 3 or less, about 2 or less, or about 1.

One or more ends of the degradable polyether may have a plurality of functional groups to allow for the binding of bioactive molecules to the polyethylene oxide. The functional group may be selected based on the target molecule to which the degradable polyether is to be bonded. In one embodiment, these functional groups may be selected from the group consisting of halogens, esters, acids, azides, hydroxyl groups, amino groups, vinyl-containing end groups, and combinations thereof. For example, these functional groups may be selected from Cl, Br, N₃、OH、O-、CH₂＝CHCH₂O-, and combinations thereof. Suitable bioactive molecules include, but are not limited to: proteins, peptides, enzymes, medicinal chemicals or organic moieties (organic moieties), and combinations thereof.

The degradable polyethers may have a well-defined structure and have a molecular weight in the range of about greater than 0kg/mol to about 50kg/mol, even up to about 850 kg/mol. In one embodiment, the degradable polyether has a molar mass of about 24kg/mol or less. In some embodiments, the degradable polyethers may have a molar mass of about 50kg/mol, about 35kg/mol or less, about 30kg/mol or less, about 25kg/mol or less, about 24kg/mol or less, about 23kg/mol or less, about 22kg/mol or less, about 21kg/mol or less, about 20kg/mol or less, about 19kg/mol or less, about 18kg/mol or less, about 17kg/mol or less, about 16kg/mol or less, about 15kg/mol or less, about 14kg/mol or less, about 13kg/mol or less, about 12kg/mol or less, about 11kg/mol or less, about 10kg/mol or less, about 9kg/mol or less, or, About 8kg/mol or less, about 7kg/mol or less, about 6kg/mol or less, about 5kg/mol or less, about 4kg/mol or less, about 3kg/mol or less, about 2kg/mol or less, or about 1kg/mol or less. In other embodiments, the degradable star polyethers have a molar mass of about 850kg/mol or less, or any value or range between 0kg/mol and 850 kg/mol.

These degradable polyethers may also have a narrow polydispersity. In one embodiment, the polydispersity index of the degradable polyethers may range from about 1 to about 1.6. For example, the polydispersity index of these degradable polyethers may be about 1.6, about 1.5, about 1.4, about 1.30, about 1.29, about 1.28, about 1.27, about 1.26, about 1.25, about 1.24, about 1.23, about 1.22, about 1.21, about 1.20, about 1.19, about 1.18, about 1.17, about 1.16, about 1.15, about 1.14, about 1.13, about 1.12, about 1.11, about 1.10, about 1.09, about 1.08, about 1.07, about 1.06, about 1.05, about 1.04, about 1.03, about 1.02, about 1.01, or about 1.00.

Fig. 1 is a flow diagram of a method of forming a degradable polyether using anionic ring-opening copolymerization according to one or more embodiments of the present disclosure. As shown in fig. 1, the method 100 may be performed by: ethylene oxide monomers 102 are contacted 101 with cyclic esters or carbon dioxide 103 in the presence of an alkyl borane and an initiator 104 to form polyethers 105 having degradable carbonate or ester linkages incorporated into the polymer backbone. A schematic of the reaction scheme for forming the degradable polyether is shown in fig. 2.

Typically, the contacting is typically by physical, direct, or intimate contact of the ethylene oxide monomer, cyclic ester, carbon dioxide, alkyl borane, and/or initiator. The contact of the components or substances may be performed simultaneously in any order or sequentially in any order, and thus is not particularly limited. Each substance may be contacted in a solvent, such as a polar solvent or a less polar solvent. For example, in one embodiment, the solvent may be selected from toluene and tetrahydrofuran, and other such solvents. The contacting may be conducted at a temperature in the range of about 0 ℃ to about 100 ℃, or any value or range thereof. Preferably, the contacting is carried out at a temperature of about room temperature, such as a temperature in the range of about 20 ℃ to about 30 ℃. The duration of the contact should be sufficient to complete the copolymerization reaction. For example, the duration of contact may range from about 1min to about 1000min, or in some cases longer.

In embodiments involving cyclic esters such as lactide, the activator and initiator may optionally be contacted with ethylene oxide monomer and cyclic ester, respectively. For example, in one embodiment, the activator and initiator may be contacted in a solvent to form a first solution, and the ethylene oxide monomer and cyclic ester may be separately contacted in a solvent to form a second solution. The first solution may then be contacted with the second solution, optionally under agitation, and the reaction allowed to proceed. In embodiments where the initiator has two components, the initiator may optionally be formed prior to contacting with the activator. For example, in one embodiment, an initiator precursor material can be contacted in a solvent to generate an initiator, and then the initiator can be contacted with an activator in the solvent to form a first solution. In embodiments involving carbon dioxide, the initiator may optionally be contacted with carbon dioxide and then dissolved in a solvent to form a first solution, and the activator may be contacted with the solvent to form a second solution. The first solution may then be contacted with the second solution, after which ethylene oxide monomer may be added and the reaction allowed to proceed (e.g., at a carbon dioxide pressure of 1 bar).

The molar ratio of ethylene oxide monomer to cyclic ester or carbon dioxide can be selected and adjusted at a selected or desired chain length to obtain degradable polyethers having different (and adjustable) ester unit or carbonate unit contents. Typically, the ethylene oxide monomer is added in stoichiometric excess relative to the cyclic ester or carbon dioxide. For example, the molar ratio of ethylene oxide monomer to cyclic ester can range from about 1.01:1 to about 10: 1. In one embodiment, the molar ratio may be about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, or any increment between these ratios.

Suitable ethylene oxide monomers include monomers of the formula:

wherein R is₁And R₂May each be independently selected from the group consisting of absent, hydrogen, alkyl, heteroalkyl, cycloalkyl, alkenyl, heteroalkenyl, cycloalkene, alkynyl, heteroalkynyl, cycloalkynyl, alkoxy, aryl, heteroaryl, aralkyl, alkylene, alkaryl, alkarylene, halogen, or combinations thereof, each of which may be substituted or unsubstituted. In some embodiments, R₁And R₂Are joined and form a fused ring, e.g., a ring structure having 5 or more carbon atoms, wherein any one of the carbon atoms may be optionally substituted with a heteroatom. Non-limiting examples of suitable ethylene oxide monomers include the following formulas:

these should not be limiting as other ethylene oxide monomers may be used herein without departing from the scope of the invention. In some embodiments, R₁And/or R₂Comprising one or more additional ethylene oxide monomers. For example, in some embodiments, the oxirane monomers can be characterized as diepoxide monomers, triepoxide monomers, and the like.

The cyclic ester may be selected from any cyclic compound (e.g., cycloalkanes, cycloalkenes, etc.) having an ester unit/group represented by the formula-C (O) O —One or more carbon atoms substituted by the group. Suitable cyclic esters include, but are not limited to: cyclic monoesters, cyclic diesters, cyclic triesters, and the like. Non-limiting examples of suitable cyclic esters include: lactide, trimethylene carbonate, glycolide, beta-butyrolactone, delta-valerolactone, gamma-butyrolactone, gamma-valerolactone, 4-methyldihydro-2 (3H) -furanone, alpha-methyl-gamma-butyrolactone, epsilon-caprolactone, 1, 3-dioxolan-2-one, propylene carbonate, 4-methyl-1, 3-dioxan-2-one, 1, 3-doxepin-2-one, 5-C_1-4Alkoxy-1, 3-dioxane-2-ones, and mixtures or derivatives thereof; any of these may be unsubstituted or substituted. In a preferred embodiment, the cyclic ester comprises lactide monomers. The lactide monomer may be selected from the group consisting of L-lactide, D-lactide, meso-lactide, and combinations thereof. The lactide monomer may be further substituted or unsubstituted. For example, the methyl groups of the lactide may be substituted with one or more substituents selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, alkenyl, heteroalkenyl, cycloalkene, alkynyl, heteroalkynyl, cycloalkynyl, alkoxy, aryl, heteroaryl, aralkyl, alkylene, alkaryl, alkarylene, halogen, or combinations thereof, any of which may be substituted or unsubstituted. The foregoing substituents should not be limiting as any substituent known to those skilled in the art may be used herein.

The activator may be selected to achieve one or more of the following objectives: selectively activate ethylene oxide monomer, form acid radical complex with initiator, inhibit ester exchange reaction and inhibit generation of cyclic carbonate. Typically, the alkylborane is added in stoichiometric excess with respect to the initiator. In one embodiment, the ratio of alkylborane to initiator may be about 5: 1. In some embodiments, the ratio of alkyl borane to initiator is in the range of about 1:1 to about 5: 1. In some embodiments, the ratio of alkylborane to initiator may be about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, or even higher. The activator used in the process described herein may be an alkylborane, such as a trialkylborane. Non-limiting examples of suitable activators include: triethylborane, triphenylborane, tributylborane, trimethylborane, triisobutylborane, and combinations thereof. In certain embodiments, the alkylborane is triethylborane.

The initiator, which forms an acid-type complex with the activator, may include salts or organic bases. Salts and organic bases may include organic cations or alkali metals associated with or mixed with anions. For example, in one embodiment, the initiator includes an organic cation associated with or mixed with an alkoxide having an organic substituent. In one embodiment, the initiator comprises an alkali metal associated with or mixed with an alkoxide having an organic substituent. In one embodiment, the initiator comprises an organic cation associated with or mixed with an azide. In one embodiment, the initiator comprises an organic cation associated with or mixed with a halogen.

The organic cation may be based on one or more of phosphazene (phosphazenium), ammonium and phosphorus. For example, in one embodiment, the organic cation may be based on a phosphazene base, such as t-Bu-P_YWherein Y is 2 or 4; or ammonium or phosphonium salts in which their nitrogen or phosphorus is linked to four alkyl groups, each of which may be the same or different. The alkali metal may include any alkali metal. For example, in one embodiment, the alkali metal may be selected from lithium, potassium, sodium, and combinations thereof. The anion may comprise any negatively charged species. For example, in one embodiment, the anion may be selected from the group consisting of hydroxyl, ester, acid, alkoxide, azide, and halogen. The alkoxide may be formed from any alcohol having at least one hydroxyl group. Any halogen may be used. For example, in one embodiment, the halogen may be selected from Cl^-And Br^-。

In one embodiment, the initiator may be selected from the following formulas:

{Y⁺,RO^-}、{Y⁺,RCOO^-}、{X⁺,N₃ ^-and { X }⁺,Cl^-}；

Wherein, Y⁺Is selected from K⁺、t-BuP₄ ⁺And t-BuP₂ ⁺；X⁺Selected from NBu₄ ⁺、PBu₄ ⁺、NOct₄ ⁺And PPN⁺；RO^-Is selected from CH₃O(CH₂)₂O(CH₂)₂O^-、H₂C＝CHCH₂O^-、

For example, the initiator may be selected from and/or prepared from p-methylbenzyl alcohol (PMBA) and t-BuP₄Diethylene Glycol Monomethyl Ether (DGME) and t-BuP₄Bisphenol A (BPA) and t-BuP₄P-methylbenzyl alcohol (PMBA) and t-BuP₂Tetrabutylammonium chloride (TBAC), bis (triphenylphosphine) imide chloride (PPNCl), tetraoctylammonium chloride (TOACl), tetrabutylphosphonium chloride (TBPCl), tetrabutylammonium azide (TBAA), and allyl alcohol and t-BuP₄。

In one embodiment, the method of forming the degradable polyether is performed as shown in the following reaction scheme:

in one embodiment, the method of forming the degradable polyether can be performed in the manner as shown in the following reaction scheme:

embodiments of the present disclosure further describe modified biomolecules comprising a bioactive molecule bound to a degradable polyether, wherein the degradable polyether has an ester unit or a carbonate unit incorporated into a polyethylene oxide backbone. Typically, these bioactive molecules are modified by covalent bonding to degradable polyethers. Additionally, the bioactive molecule can be selected from the group consisting of proteins, peptides, enzymes, pharmaceutical chemicals or organic moieties, and combinations thereof. The degradable polyether may include any of the copolymers of the present invention.

Fig. 3 is a flow diagram of a method of forming a degradable star polyether according to one or more embodiments of the present disclosure. As shown in fig. 3, the method 300 may proceed as follows: the diepoxide monomer is contacted with carbon dioxide and/or a cyclic ester in the presence of an initiator and a first amount of an alkyl borane 301. In this step, the diepoxide monomer may be copolymerized (e.g., by anionic ring-opening copolymerization) with carbon dioxide and/or a cyclic ester to obtain a multifunctional core containing carbonate units and/or ester units. For example, carbonate units may be derived from carbon dioxide, thereby creating degradable carbonate linkages. Ester units may be derived from cyclic esters, thereby creating degradable ester linkages. The presence of carbonate units and/or ester units may impart degradability to the multifunctional core product. Examples of such multifunctional cores include, but are not limited to: polycarbonate cores, polyether cores, polyester cores, and the like.

The contacting 301 may be carried out by adding, sequentially or simultaneously in any order, an initiator, a solvent, an alkyl borane, a diepoxide monomer, carbon dioxide, and/or a cyclic ester to a reaction vessel, which may be carried out under mechanical agitation. For example, in some embodiments, a suitable preparation sequence includes sequentially adding the initiator to the reaction vessel, followed by sequentially adding the solvent, the alkyl borane, and the diepoxide monomer with or without mechanical agitation. After one or more of the above components are added, carbon dioxide or a cyclic ester may be added to the reaction vessel, and copolymerization may be allowed to proceed. During or through the copolymerization, the epoxy rings of the diepoxide monomer may be opened and may each be copolymerized with carbon dioxide and/or cyclic esters in the presence of an initiator and an alkylborane. In this manner, the diepoxide monomer may act as a cross-linking agent to link at least two polymer chains, each formed by copolymerization.

Suitable initiators, solvents and/or alkylboranes are described above and will not be repeated here. The diepoxide monomer may be selected from any monomer comprising at least two epoxides. Examples of suitable diepoxide monomers include vinylcyclohexene dioxide (vinyl cyclohexene dioxide) and derivatives thereof. Other suitable diepoxide monomers include, but are not limited to: butadiene dioxide; 1,2,3, 4-diepoxybutane; 1,2,7, 8-diepoxyoctane; 1,2,5, 6-diepoxy resin cyclooctane; dicyclopentadiene diepoxide; polyethylene glycol diglycidyl (poly (ethylene glycol diglycidyl)); diglycidyl ethers such as glycerol diglycidyl and diglycidyl ethers such as 1, 3-propanediol, 1, 4-butanediol, 1, 6-hexanediol, cyclohexane-1, 4-diol, cyclohexane-1, 1-dimethanol, cyclohexane-1, 2-dimethanol, cyclohexane-1, 3-dimethanol, cyclohexane-1, 4-dimethanol, diethylene glycol, hydroquinone, resorcinol, 4-isopropylidenediphenol, naphthalenediol, and the like; or a derivative thereof. Although these diepoxide monomers are described, other multifunctional epoxides may be used herein, including, for example, triepoxide compounds and the like.

The extent or degree of crosslinking affects the degradability of the multifunctional core formed. For example, a high degree of crosslinking may not result in a degradable multifunctional core to form a gel, although it may be based on the choice of reagents and reaction conditions, among others. Thus, it is desirable to maintain or maintain the extent or degree of crosslinking of the diepoxide monomer at low to moderate levels when copolymerization is carried out. This can be achieved, for example, by using as low as an intermediate amount of the diepoxide monomer. For example, in some embodiments, the molar ratio of the diepoxide monomer to the initiator is controlled to be less than about 10, but not greater than about 20. For example, the molar ratio of the diepoxide monomer to the initiator may be about 20 or less, about 19 or less, about 18 or less, about 17 or less, about 16 or less, about 15 or less, about 14 or less, about 13 or less, about 12 or less, about 11 or less, preferably about 10 or less, about 9 or less, about 8 or less, about 7 or less, about 6 or less, or more preferably, about 5 or less, about 4 or less, about 3 or less, about 2 or less, or any value or range therein.

The volume ratio of the diepoxide monomer to the solvent may be in the range of about 1:1 to about 1: 10. For example, in some embodiments, the volume ratio of the diepoxide monomer to the solvent is about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, about 1:5.5, about 1:6, about 1:6.5, about 1:7, about 1:7.5, about 1:8, about 1:8.5, about 1:9, about 1:9.5, or about 1:10, or any range or value therebetween.

The carbon dioxide may be added to the reaction vessel at a pressure in the range of about 0.01 bar to about 25 bar. For example, in some embodiments, the carbon dioxide may be added at a pressure in the range of about 5 bar to about 15 bar (preferably about 10 bar). In other embodiments, the carbon dioxide is added at a pressure of about 1 bar, about 2 bar, about 3 bar, about 4 bar, about 5 bar, about 6 bar, about 7 bar, about 8 bar, about 9 bar, about 10 bar, about 11 bar, about 12 bar, about 13 bar, about 14 bar, about 15 bar, about 16 bar, about 17 bar, about 18 bar, about 19 bar, about 20 bar, about 21 bar, about 22 bar, about 23 bar, about 24 bar, or about 25 bar, or any value or range therein.

The temperature at which step 301 is carried out may range from about 0 ℃ to about 100 ℃. In some embodiments, the contacting is conducted at a temperature in the range of from about 50 ℃ to about 80 ℃. For example, the contacting can be performed at a temperature of about 50 ℃, about 51 ℃, about 52 ℃, about 53 ℃, about 54 ℃, about 55 ℃, about 56 ℃, about 57 ℃, about 58 ℃, about 59 ℃, about 60 ℃, about 61 ℃, about 62 ℃, about 63 ℃, about 64 ℃, about 65 ℃, about 66 ℃, about 67 ℃, about 68 ℃, about 69 ℃, about 70 ℃, about 71 ℃, about 72 ℃, about 73 ℃, about 74 ℃, about 75 ℃, about 76 ℃, about 77 ℃, about 78 ℃, about 79 ℃, or about 80 ℃, or any value or range therebetween. Additionally, the contacting can be performed for a period of time of up to about one week or less, preferably less than about 24 hours, or more preferably less than about 17 hours, for example about 15 hours.

The arms that degrade the star polyether may be polymerized while the multifunctional core is formed and the reaction vessel is optionally allowed to cool in step 301. Thus, in step 302, the degradable multifunctional core from step 301 is contacted with an ethylene oxide monomer in the presence of a second amount of an alkylborane. In a subsequent reaction, ethylene oxide monomers are polymerized to form arms of polyether attached to the degradable multifunctional core, thereby forming a degradable star polyether. In some embodiments, the arms of the star polyether are chemically identical, thereby forming a star polymer. In some embodiments, two or more ethylene oxide monomers are reacted, or monomers other than ethylene oxide monomers are reacted, to form heterotypic star polymers with different arms, or star polymers with arms comprising copolymers (e.g., block copolymers), and other types of polymers.

To form the arms of the star polyether, ethylene oxide monomer may be added to the reaction vessel. Suitable ethylene oxide monomers are described above and therefore will not be repeated here. In some embodiments, the solution comprising ethylene oxide monomer, solvent, and a second amount of alkyl borane are injected into the reaction vessel after unreacted carbon dioxide is vented or released. In embodiments involving a cyclic ester, the reaction in step 301 may be allowed to proceed until the cyclic ester is completely or completely consumed, or unreacted cyclic ester may be separated and/or removed from the reaction vessel. After the ethylene oxide monomer, solvent, and second amount of alkyl borane are added, the polymerization reaction may be allowed to proceed (optionally with mechanical agitation) to form the polyether arms of the star polymer.

The volume ratio of ethylene oxide monomer to solvent may range from about 1:1 to about 1: 20. For example, in some embodiments, the volume ratio of ethylene oxide monomer to solvent is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, or about 1:20, preferably about 1:5 to about 1:15, or more preferably about 1: 10.

Although not required, in some embodiments, in step 301 of the process of the present invention, the alkylborane is charged to the reaction vessel in stoichiometric amounts with the initiator, and each reacts to form an acid-based complex that can be used to activate the copolymerization in step 301. In certain instances, the second amount of alkylborane of step 302 may be added to the reaction vessel such that the alkylborane is present in a stoichiometric excess to activate the ethylene oxide and ring-opening polymerization. In some embodiments, an excess of alkylborane may be used to activate the ethylene oxide monomer in the polymerization of the polyether arms. In some embodiments, the first amount and the second amount of the alkylborane are the same. In some embodiments, the first amount of alkylborane is different from the second amount. For example, in some embodiments, the first amount of alkylborane is less than the second amount. In some embodiments, the first amount of the alkyl borane is greater than the second amount.

In some embodiments, the molar ratio of multifunctional core to alkyl borane can be selected or maintained in the range of from about 1:1 to about 1:10 upon contact 302 or during polymerization of the entire ethylene oxide monomer, or both. For example, in some embodiments, the molar ratio of multifunctional core to alkylborane is selected or maintained at about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, about 1:5.5, about 1:6, about 1:6.5, about 1:7, about 1:7.5, about 1:8, about 1:8.5, about 1:9, about 1:9.5, or about 1:10, or any value or range therein. Preferably, the molar ratio of the diepoxide monomer to the alkylborane is in the range of about 1:3 to about 1:5, or any value therein, more preferably about 1:3.

The temperature at which step 302 is performed may range from about 0 ℃ to about 100 ℃. In some embodiments, the contacting is performed in the range of about 30 ℃ to about 50 ℃. For example, the contacting can be performed at a temperature of about 30 ℃, about 31 ℃, about 32 ℃, about 33 ℃, about 34 ℃, about 35 ℃, about 36 ℃, about 37 ℃, about 38 ℃, about 39 ℃, about 40 ℃, about 41 ℃, about 42 ℃, about 43 ℃, about 44 ℃, about 45 ℃, about 46 ℃, about 47 ℃, about 48 ℃, about 49 ℃, or about 50 ℃, or any value or range therebetween. Preferably, the polymerization is carried out at a temperature of about 40 ℃. Additionally, the contacting may be carried out for a period of time of up to about one week or less, preferably about 24 hours or less.

In a further step 303 (not shown), the reaction mixture from step 302 may be quenched with an acid (e.g., HCl) dissolved in an alcohol (e.g., methanol). To obtain a fine-grained product, the crude product can be dissolved and/or precipitated in diethyl ether, then centrifuged and dried.

The following examples are intended to illustrate the above invention and should not be construed as narrowing the scope thereof. Those skilled in the art will readily recognize that the examiner suggests many other ways in which the invention may be practiced. It should be understood that many variations and modifications may be made while remaining within the scope of the present invention.

Example 1

Preparation of degradable polyethylene oxides by anionic copolymerization of ethylene oxide with L-lactide

The following examples describe a convenient method for preparing degradable polyethylene oxide (PEO). Very low levels of LLA were randomly incorporated into the backbone of PEO by anionic copolymerization of ethylene oxide with L-lactide (LLA) in the presence of triethylborane. The reactivity of LLA is reduced and the transesterification reaction is suppressed by means of the Lewis acid of triethylborane. The copolymerization of EO with LLA produces poly (EO-co-LLA) samples with low to moderate ester unit content, controlled molar mass and narrow polydispersity. Reactivity ratios were determined using the Kelen-Dudos method and the Meyer-Lowry end model method. The resulting copolymers were further investigated by Differential Scanning Calorimetry (DSC); hydrolysis experiments were performed to show the degradability of these PEO samples.

The objective of the work presented in this example is to incorporate as low as a very low percentage of LLA units into PEO chains by anionic copolymerization of EO with LLA, thereby imparting degradability to these PEO chains without changing their inherent properties of hydrophilicity, crystallinity, etc. The role of triethylborane in the anionic copolymerization of EO with LLA was specifically studied. Unlike the coordination catalytic approach that provides broad molar mass distribution and structural uncertainty for LLA-EO copolymers, the boron activated anionic copolymerization of EO with LLA produces well-defined poly (EO-co-LLA) samples that show narrow polydispersity and tunable content of EO and LLA units (see flow chart below). The following scheme illustrates the reaction scheme for the anionic ring-opening polymerization of ethylene oxide with L-lactide using triethylborane as activator.

Experimental part

General procedure

All reactions were carried out in a Braun Labmaster glove box under a dry, oxygen-free argon atmosphere. Ethylene Oxide (EO), L-lactide (LLA), Diethylene Glycol Monomethyl Ether (DGME), p-methylbenzyl alcohol (PMBA), bisphenol A (BPA), t-BuP₄、t-BuP₂(tert-butylammonium chloride) TBACl,) (bis (triphenylphosphine) imide chloride) tetrabutylammonium (PPNCl), tetraoctylammonium chloride (TOACl), tetrabutylphosphonium chloride (TBPCl), tetrabutylammonium azide (TBAA), Allyl alcohol (Allyl A) were purchased from Aldrich (Aldrich). Tetrahydrofuran (THF) and toluene (Tol) were distilled over the sodium/benzophenone mixture before use. After stirring for two days, the 1, 4-dioxane was placed in CaH₂Distillation is carried out above. By oxidation of ethylene in CaH₂The ethylene oxide was purified by stirring one day above and distilled into a flask containing n-butyl lithium (n-BuLi). It was then stirred for several hours, followed by further distillation. The LLA was purified by recrystallization from ethyl acetate twice, followed by freeze-drying from dried dioxane. Diethylene glycol monomethyl ether is purified by azeotropic distillation from toluene. PMBA and BPA were freeze dried from dioxane. In CDCl₃In (1), all¹H and¹³c NMR spectra were recorded on a nuclear magnetic resonance analyzer (Bruker AVANCE III-400 MHz). Traces of GPC were recorded using a gel permeation chromatograph equipped with a Styragel HR2 column (VISCOTEK VE2001) using Tetrahydrofuran (THF) as the eluent (flow rate 1 mL/min). Using a narrow molecular weight distribution (M)_w) The polystyrene standard of (a). DSC measurements were carried out in an air atmosphere using a MettlerToledo differential scanning calorimeter (Mettler Toledo DSC1/TC 100). The sample was first heated from room temperature RT to 200 ℃ to eliminate thermal history, then cooled to-100 ℃ at a heating/cooling rate of 10 ℃/min, and finally heated again to 200 ℃. This cycle was repeated until constant melting and cooling temperatures (Tm and Tc) were recorded.

Representative procedure for the synthesis of poly (EO-co-LLA) using tetrabutylammonium chloride (TBACl) as initiator: a pre-dried 30mL glass Hilbert tube (Schlenk tube) (80 mm. times.28 mm) consisting of a three-way stopcock and equipped with a magnetic stir bar was used. About 86 μ L of triethylborane (about 0.086mmol) was first added to a solution of TBACl (about 4.8mg, about 0.017mmol) dissolved in toluene (about 0.5mL) in a glass Hilbert tube under an argon atmosphere. A premixed solution of LLA (about 100mg, about 0.69mmol) and ethylene oxide (about 150mg, about 3.47mmol) dissolved in toluene (about 1mL) was then added to the initiator-borane system. The polymerization was carried out at room temperature (about 25 ℃ C.) for 4 hours with stirring. The reaction was then quenched with a few drops of 5% HCl in methanol and the polymer was precipitated in cold diethyl ether. The polymer obtained after filtration was dried in a vacuum oven and characterized by GPC and NMR.

Representative procedure for the Synthesis of Poly (EO-co-LLA) Using t-BuP4 initiator: this reaction was carried out using a pre-dried 30mL glass Hilbert tube (80 mm. times.28 mm) consisting of a three-way stopcock and equipped with a magnetic stirrer. A solution of PMBA (about 4.3mg, about 0.035mmol) in toluene (about 0.5mL), a solution of t-BuP4 (about 35. mu.L, about 0.035mmol) was added to the reaction flask under an argon atmosphere and stirred at room temperature for several minutes. Then triethylborane (about 176. mu.L, about 0.176mmol) and a solution of LLA (about 75mg, about 0.520mmol) and ethylene oxide (about 152mg, about 3.47mmol) in premixed monomer toluene (about 1mL) were added sequentially to the initiator-borane system and polymerization was carried out with stirring at about room temperature for about 1 hour. The reaction was quenched with a few drops of 5% HCl in methanol and precipitated in cold diethyl ether. The polymer obtained after filtration was dried in a vacuum oven and characterized by GPC and NMR.

Results and discussion

Copolymerization of ethylene oxide with L-lactide

Because EO and LLA exhibit very different reactivities and because the monomer units corresponding to LLA are susceptible to transesterification under anionic conditions, EO and LLA cannot be copolymerized even using a weak base as an initiator. For example, in alcohols and weak bases (such as t-BuP)₂) In the presence of (A), it takes about 3 days to complete the copolymerization of EO, while it takes only about 1 minute to complete the conversion of LLA under the same conditions. This has been the main reason for the copolymerization of these two monomers using coordination chemistry.

This example presents a new approach to the copolymerization of EO and LLA, which is not based on purely anionic species, but on acid-based complexes involving a Lewis acid (i.e., triethylborane) and a base (which is usually an alkoxide)₂This is usually achieved using purely ionic species. Similarly, it has been found that borate-based complexes are very effective for initiating and causing controlled copolymerization of azidoglycidyl ethers, which are epoxide monomers that have never been polymerized before. In each of the two examples described above, in addition to the borate-based complex, a free trialkylboron must be added to activate the monomer for polymer generation, since the addition of the complex generally does not have sufficient nucleophilicity.

Initial attempts to use PMBA/t-BuP₄As initiator system and TEB as lewis acid to form an acid-based complex leading to copolymerization, thereby homopolymerizing EO and LLA. Both were homopolymerized in the presence of excess TEB (5eq.) to activate the monomer. In the case of EO, samples with the predicted molecular weights were provided, as expected, in either tetrahydrofuran or toluene: it is evident that the presence of free TEB is essential for triggering the copolymerization (

items

1 and 2 of Table 1). In contrast, in the case of LLA (see the flow chart immediately above), although excess TEB was present (5eq.) hardly any homopolymerization was observed (conversion was below 1%), and the addition of further excess TEB did not contribute to increase the conversion of LLA (

entries

3 and 4 of table 1).

Interestingly, monomers like LLA, which homopolymerize very quickly when exposed to purely ionic species, remain in place and do not undergo ring opening in the presence of borate-based acid-based complexes. Next, the copolymerization of LLA and EO in the presence of 5 eq.TEB was investigated. About 15-20 mol% of LLA was charged to the reaction medium to see if low levels of ester could be incorporated into the PEO backbone. In all the following experiments toluene as a non-polar solvent was used for the copolymerization of EO with LLA. After polymerization, the reaction mixture was poured into cold ether to collect all polymer product, which was characterized by GPC and NMR. FIG. 4 shows a representative¹H NMR spectrum. Characteristic peaks for LLA and EO units are clearly detected at 5.2 and 1.5ppm (peaks a, b) and at 3.5ppm (peak c), indicating the incorporation of ester units. The peaks g and h at 4.3ppm and 4.10ppm correspond to the-CH units at EO and LLA, respectively₂CH₂OOCCH(CH₃)OOCCH(CH₃) Methylene proton of EO and methine proton of LLA linked between O-and OCCH (CH) units between LLA and EO₃)OOCCH(CH₃)OCH₂CH₂Methine protons of LLA units linked between O-groups, as shown in FIG. 4. Two kinds of polymerizationThe presence of characteristic peaks and connecting peaks of PEO and LLA units, illustrates the formation of random copolymers. The integral ratio of peak g to peak h is close to 3, indicating that the transesterification reaction of LLA is negligible. Based on the NMR data, the LLA unit content can then be calculated and the molar mass of the copolymer obtained can be estimated using the peaks of the initiator p-methylbenzyl alcohol (peaks d, e, f at 4.5, 7.1, 2.3 ppm) as reference (see the relevant data listed in Table 1). Using the formula L_LLA＝(SI_5.21 _ppm+2SI_4.10 _ppm)/2SI_4.10ppm can determine that the average segment length of the PLLA is equal to about 1.57, where SI is the integrated intensity of each peak. This means that on average less than two LLA units are found adjacent along the polymer backbone, confirming the reactivity ratio (r) of LLA_LLA) The value of (a) is very low. Copolymerization was initiated according to the same procedure using the PMBA/t-BuP4 system in the presence of TEB, with different molar masses being targeted (Table 1, items 6 to 12). The values of the molar masses of the various samples obtained from NMR are close to the theoretical values; molar masses of up to 24kg/mol are achieved and the ester content is kept at about 5% under all conditions. When the charge ratio of LLA to EO was varied, the ester content in the resulting copolymer was varied (entry 11 of Table 1). Analysis of the obtained copolymer sample by GPC showed a monomodal shape and a narrow molar mass distribution (fig. 5); the latter is close to the theoretical value and the value generated by NMR calculation. It was thus demonstrated that EO copolymerizes with LLA in an "active" manner under these conditions and that the transesterification reaction is completely inhibited.

It is believed that not only was the first successful attempt to copolymerize different monomers like EO and LLA under "living" conditions, but it also proved that very low levels of ester linkages could be incorporated into the polyether chain, a achievement that has never been achieved. When the reaction was carried out in THF, which is a less polar solvent, item 5 in table 1, a loss of control of the molar mass of the copolymer sample was observed, indicating the occurrence of transesterification and thus the high probability of back-biting reactions.

In addition to the polymerization initiated with the PMBA/tBuP4 system in the presence of TEB for copolymerization, other organic initiators, ammonium and phosphorus halides (e.g., TBACl and TBPCl), were also used. Similar results were obtained, but the ester content inside the isolated copolymer tended to be slightly higher than the copolymer produced in the alkoxide/tBuP 4 system (

entries

15, 19 and 20 of Table 1). This may be due to the difference in reactivity between EO and LLA in the presence of various cations associated with the alkoxide (see below). Difunctional and heterodifunctional copolymers are also prepared using various initiators. For example, when bisphenol a was used as the initiator, two hydroxyl-terminated PEO were obtained, which included about 3% ester content (item 13 of table 1); if the reaction is started with allyl alcohol and tetrabutyl azide as initiators (

items

21 and 22 of Table 1), a sample of copolymer with vinyl and azide end groups is generated (FIG. 6), which is a meaningful and powerful functional group for bio-binding and applications.

TABLE 1 random copolymerization results of EO and LLA Using different initiation systems

P-methylbenzyl alcohol (PMBA) is reacted with P, unless otherwise indicated₄And P₂Used together, P₄＝t-BuP₄，P₂＝t-BuP₂，^aDiethylene glycol monomethyl ether is used as the alcohol,^bbisphenol a is used as the alcohol.^cM_n(theo)＝(mp/N1)，m_pTotal recovered weight of polymer, N_IMoles of initiator.^dThe ester content and Mn (NMR) are calculated on the basis of¹HNMR。^eGPC measurements were performed with THF as the eluent and polystyrene standards as calibration.

To characterize the properties of the copolymers prepared, kinetic data were collected and the monomer conversion was determined using PMBA/tBuP4, TBACl and PPNCl, respectively, as initiators at the same initial feed ratio. The relevant polymerization data are listed in table 2. The ester content gradually increases with increasing polymerization time (although well below the ether content)Rate), indicating that EO is consumed much faster. Reactivity ratio values rEO and rLLA were calculated and trends for self-growth or incorporation of other monomers were determined by terminating the copolymerization at different time intervals and analyzing the composition of the corresponding copolymers. Reactivity ratios can be calculated using various methods, including the meo-Lewis (Mayo-Lewis) integration method, the french-Ross (Fineman-Ross) method, and the kelen-du donos method, among others. In the present embodiment, the reactivity ratio is calculated by the kelen-dudos method. Reactivity ratio r of EO in the case of tBuP 4/alkoxide System_EOA reactivity ratio value r of LLA of 6.27_LAWas 0.08. In the case of using TBACl as an initiator, r was found_EOIs 1.67, r_LLAIs 0.15 (see fig. 7-9). At the same feed ratio, the reactivity of EO decreases as the size of the cation associated with the alkoxide decreases, so more ester units are incorporated. However, in both cases, the reactivity of EO is much higher than that of LLA, which leads to low LLA content in the obtained copolymer poly (EO-co-LLA) and in very short ester segments.

TABLE 2 copolymerization results of EO and LLA with different conversions

Unless otherwise stated, PMBA and P are used₄Used together, P₄＝t-BuP₄，^aM_n(theo)＝(mp/N_I)，m_pTotal recovered weight of polymer, N_IMoles of initiator.^bEster content and M_n(NMR)Is based on¹HNMR。^cGPC measurements were performed with THF as the eluent and polystyrene standards as calibration.

Since the Kerendu method works best for instantaneous compositions and rather low conversions, a non-terminal model (BSL) was used to determine the reactivity ratios r of the two monomers_EOAnd r_LLA. The model assumes that the reactivity of the propagating species depends only on the reactivity of the incoming monomer, and ignores that of the last monomer characterized by the active speciesA property; it is suitable until complete conversion. The results of the calculation of the reactivity ratios based on the data shown in table 3 are approximately: when P4+ is used as a counter cation, r_LLA＝0.17±0.04、r_EO5.37 ± 0.4; for TBA⁺In other words, r_LLA＝0.49±0.08、r_EO2.07 ± 0.25; for PPN⁺In other words, r_LLA＝0.14±0.01，r_EO6.61 ± 0.67. In the three cases studied with three different cations (P4+, TBA +, PPN +), the product r of the reactivity ratios_EO×r_LLAVery close to 1, thereby utilizing¹H NMR confirmed this feature, which indicates the formation of a gradient copolymer. Attempts have also been made to determine the reactivity ratio using the ML's end model (rEO vs LLA). It is assumed that the copolymers formed have gradient properties and no tendency to block or alternate. We derived a simple relationship of reactivity ratios as a function of conversion from Lowry and Meyer's general formula for copolymer conversion dependence. Thus, the end model of ML provides for the copolymerization of EO with LLA in the presence of TEB, and the following reactivity ratio values: for P4⁺Wherein rLLA is 0.19 ± 0.02, rEO is 5.15 ± 0.556; for TBA⁺In other words, r_LLA＝0.50±0.07、r_EO2.03 ± 0.27; for PPN⁺In other words, r_LLA0.15 ± 0.01, rEO ═ 6.49 ± 0.46 (table 3).

TABLE 3 reactivity ratios calculated by different methods

As an aim of this study, the incorporation of ester units in the PEO chain was controlled as precisely as possible and, if possible, limited to a percentage (-5%), and the thermal properties of the obtained copolymer samples were examined using DSC. The melt transitions of both PEO were determined and compared to the melt transition of pure PEO, and as more ester units were incorporated into the PEO backbone, the melt temperature (T) of the resulting copolymer was determined_m) And gradually decreases. When about 3% of ester is incorporated, T_mFrom 58.9 ℃ to about 523 ℃ in the presence of a catalyst. When ester bonds were further increased to about 7%, T_mReduced to about 38.5 ℃; when about 14% of the ester units are incorporated, then T_mTo about 28.6 deg.c (fig. 10). In the latter case in particular, a significantly cold crystallization transition temperature at about-17.6 ℃ is measured due to the incorporation of more ester units. However, no melting transition temperature of PLLA was detected, even though the sample contained about 14% ester, indicating the incorporation of very short PLLA segments along the PEO backbone. In contrast, in the case of a multi-block poly (EO-co-LLA) copolymer containing about 17% ester units, the melting temperature (T) of PLLA was determined unambiguously_m)。

Finally, poly (EO-co-LLA) was subjected to degradation to check the average length of PEO segments. The copolymer was dissolved in a 40:60 methanol: water solution of about 0.5M NaOH and stirred for about two days to hydrolyze the ester bonds. By using¹H NMR characterized the polymer recovered after this treatment, indicating complete degradation and disappearance of the ester bond. The molar mass of the degraded PEO was analyzed by GPC. As shown in FIG. 11, the molar mass of the copolymer sample decreased from the initial about 24Kg/mol to about 3 Kg/mol.

In summary, degradable polyethylene oxides with low polydispersity and well-defined structure are directly prepared in a controlled manner by anionic ring-opening copolymerization of EO with LLA. The presence of TEB selectively increases the reactivity of EO and inhibits transesterification reactions. The method is versatile and can be used not only to synthesize functionalized linear PEO species, but also to synthesize branched PEO species with high molar mass and without fear of degradability problems. Furthermore, metal-free synthesis makes this method more likely for biomedical use.

Example 2

Preparation of degradable polyethylene oxides by anionic copolymerization of ethylene oxide with lactide or carbon dioxide

The scheme shown below shows the formation of degradable PEG in a direct manner by anionic copolymerization of EO with lactide or carbon dioxide in the presence of trialkylborane. As described in this example, the random incorporation of very low levels (about 5%) of lactide and carbon dioxide results in the formation of ester or carbonate linkages within the PEG backbone, which imparts degradability to the resulting PEG; in addition, the copolymers obtained retain their hydrophilicity and a well-defined structure. This allows the preparation of heterobifunctional capped degradable PEGs, or derivatized to bind molecules useful in the biological field.

Method

Representative procedure for the synthesis of poly (ethylene oxide) -co- (L-Lactide) (poly (ethylene oxide) -co- (L-lactde)) using TBACl as initiator: a pre-dried 30mL glass Hibutack tube (80mm k tube) consisting of a stopcock and equipped with a magnetic stirrer was used to carry out this reaction. In an argon atmosphere, 86 μ L of triethylborane (0.086mmol) was first added to a solution of TBACl (4.8mg, 17 μmol) in toluene (0.5mL) in a glass Hilbert tube. A pre-mixed solution of L-lactide (100mg, 0.69mmol) and ethylene oxide (150mg, 3.47mmol) in toluene (1mL) was then added to the initiator-borane system. The polymerization was carried out at room temperature (about 25 ℃ C.) for 4 hours with stirring. Then, the reaction was quenched by a few drops of 5% HCl in methanol and the polymer solution was precipitated in cold diethyl ether. After filtration, the obtained polymer was dried in a vacuum oven and characterized by GPC and NMR.

Representative procedure for the synthesis of poly (ethylene oxide) -co- (L-lactide) using P4 as initiator: this reaction was carried out using a pre-dried 30mL glass hebrew tube (80mm x 28mm) consisting of a stopcock and equipped with a magnetic stirrer. A solution of p-methylbenzyl alcohol (PMBA) (4.3mg, 35. mu. mol) in toluene (0.5mL) and a solution of t-BuP4 (44. mu.L, 0.044mmol) were added to a reaction flask under an argon atmosphere, and stirred at room temperature for several minutes. Then triethylborane (176. mu.L, 0.176mmol) and a solution of L-lactide (75mg, 0.520mmol) and ethylene oxide (152mg, 3.47mmol) in premixed monomer in toluene (1mL) were added successively to the initiator-borane system and copolymerization was carried out at room temperature for 1 hour with stirring. The reaction was quenched with a few drops of 5% HCl in methanol and precipitated in cold diethyl ether. The polymer obtained after filtration was dried in a vacuum oven and characterized by GPC and NMR.

Representative procedure for the synthesis of poly (ethylene oxide) -co- (ethylene carbonate) using TBACl as initiator: this reaction was carried out using a pre-dried 30mL glass hobber tube (80mm x 28mm) consisting of a stopcock and a septum and equipped with a magnetic stirrer. 27.8mg of TBACl (100. mu. mol) were initially added in a dry carbon dioxide atmosphere and subsequently dissolved in 2mL of THF. Triethylborane and EO (1mL, 20mmol) dissolved in THF (150. mu.L, 0.15mmol) were injected into the tube sequentially. The copolymerization is carried out at a carbon dioxide pressure of 1 bar and at room temperature for 12 hours. The reaction was quenched with a few drops of 5% HCl in methanol and precipitated in cold diethyl ether. The polymer obtained after filtration was dried in a vacuum oven and characterized by GPC and NMR.

FIGS. 13-24 present some of the items given in Table 4¹H NMR spectrum and GPC spectrum.

Table 4: EO with LLA and CO, respectively₂As a result of random copolymerization

Para-methylbenzyl alcohol (PMBA) is used in combination with P4 and P2, P being P, unless otherwise indicated₄＝t-BuP₄，P₂＝t-BuP₂The term "l-lactide", EO-ethylene oxide, THF-tetrahydrofuran, Tol-toluene, TBACl-tetrabutylammonium chloride, PPNCl-bis (triphenylphosphine) imine chloride, Tol-tetraoctylammonium chloride, tbpci-tetrabutylphosphonium chloride, TBAA-tetrabutylammonium azide. GPC measurements were performed with THF as the eluent and polystyrene standards as calibration.^a _.The use of bisphenol a as the alcohol is preferred,^b _.diethylene glycol monomethyl ether is used as the alcohol.^c _.Polymerization at 1 bar CO₂The reaction is carried out in an atmosphere.^d _.The polymerization was carried out under an atmosphere of 2 bar of CO 2.^e.Polymerization at 4 bar CO₂The reaction is carried out in an atmosphere.

Example 3

Synthesis of star-shaped PEO with degradable polycarbonate core

The first method was used to prepare degradable PEO from a core, where the core was composed of carbonate linkages to impart degradability, as shown in fig. 12. Here, Vinylcyclohexene Dioxide (VDOX) as diepoxide is used as crosslinker by reaction with CO₂To form degradable polycarbonate cores. To obtain soluble polycarbonate cores with low degrees of crosslinking, very low amounts of diepoxide are used and the ratio of VDOX to onium salt initiator is kept below about 10. Once the nucleus is formed, then at CO₂After being gradually released, ethylene oxide was injected into the same Parr reactor along with THF solvent, followed by polymerization of ethylene oxide with the resulting polycarbonate core at about 40 ℃ with stirring. The polymerization conditions and results are listed in table 5.

Representative procedure for the synthesis of star-shaped polyethylene oxides from polycarbonate cores (PVDOX-EO) using the core-first method: the reaction was carried out in a 100mL Parr reactor with a built-in addition port, which was dried overnight at 120 ℃ and then evacuated in a glove box for about 3 hours. To illustrate the synthesis process, a star-shaped PEO sample (entry 27 in Table 5) designated PVDOX1-EO1 was used as a representative. PPNCl (0.114g, 0.2mmol) was first added to the reactor followed by THF (about 2.5mL) and TEB (0.2mL, about 1 eq). Vinylcyclohexene dioxide (about 0.14g, about 1mmol) was introduced into the reaction mixture, then the reactor was closed and removed from the glove box for CO at about 10 bar₂The addition was carried out under pressure. The polymerization was carried out at a temperature of about 80 ℃ for about 15 hours. After cooling the reactor, the CO is introduced₂Slowly released to a minimum level, EO (about 2.6mL, about 60mmol), TEB (about 0.6mL) and THF (about 20mL)Was charged into the reactor through the charging hole, and polymerization was carried out at about 40 ℃ for about 15 hours. Finally, the reaction mixture was quenched with a solution of hydrochloric acid in methanol (about 1 mol/L). The resulting crude product was purified by precipitation in diethyl ether and centrifuged and dried in a vacuum oven at about 40 ℃ for about 15 hours to obtain the final product (yield about 90%).

FIGS. 25-29 provide some of the items given in Table 5 below¹H NMR spectrum and GPC spectrum.

TABLE 5 summary of PVDOX-EO Star polymers synthesized using the precore method^a

^a.Using PPNCl as initiator, at 50-80 deg.C and 10 bar CO₂Preparation of PVDOX was carried out under ambient conditions, except where otherwise stated, with a volume ratio of VDOX/THF of 1:2.5, followed by polymerization of the resulting core with EO (40 ℃, for 24h) while maintaining a ratio of PVDOX to TEB of 1:3 and a volume ratio of EO/THF of 1: 10.^b _.The determination was carried out by GPC using polystyrene standards as reference and THF as eluent.^c.Measured by GPC equipped with multi-angle laser light scattering (GPC-MALLS).^d.N_am＝M_W,LSX arm_wt％/M_n,PEO。^e.The ratio of VDOX/THF was 1:2.^f.Monofunctional aldehyde group CHO was added to the crosslinker so that the ratio of VDOX/CHO was 1:1 and the ratio of VDOX/THF was 1: 2.5.^g.By NBu₄The polymerization was initiated with Cl and the reaction was continued at 80 ℃ for 3 h.

Other embodiments of the disclosure are possible. While the above description contains many specificities, these should not be construed as limiting the scope of the disclosure, but as merely providing illustrations of some of the presently preferred embodiments of this disclosure. It is also contemplated that various combinations or subcombinations of the specific features and aspects of the embodiments may be made and still fall within the scope of the disclosure. It should be understood that various features and aspects of the disclosed embodiments can be combined with or substituted for one another in order to form varying embodiments. Thus, it is intended that the scope of at least some of the present disclosure should not be limited by the particular disclosed embodiments described above.

Accordingly, the scope of the present disclosure should be determined by the appended claims and their legal equivalents. Accordingly, it is to be understood that the scope of the present disclosure fully encompasses other embodiments that may become obvious to those skilled in the art and that the scope of the present disclosure is accordingly to be limited by nothing other than the appended claims, in which reference to an element in the singular is not intended to mean "one and only one" unless explicitly so stated, but rather "one or more". All structural, chemical and functional equivalents to the elements of the above-described preferred embodiment that are known to those of ordinary skill in the art are expressly written herein by reference and are intended to be covered by the claims. Furthermore, it is not necessary for a device or method to address each and every problem sought to be solved by the present disclosure, for it to be encompassed by the present claims. Furthermore, no element, component, or method step in the present disclosure is intended to be dedicated to the public regardless of whether the element, component, or method step is explicitly recited in the claims.

The foregoing description of various preferred embodiments of the disclosure has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure to the precise embodiments, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments described above were chosen and described in order to best explain the principles of the disclosure and its practical application, to thereby enable others skilled in the art to best utilize the disclosure in various embodiments and with various modifications as are suited to the particular use contemplated. It is intended that the scope of the disclosure be defined by the claims appended hereto.

Various embodiments have been described. These and other embodiments are within the scope of the following claims.

Claims

1. A method of forming a degradable polymer comprising:

Contacting an ethylene oxide monomer with carbon dioxide or a cyclic ester in the presence of an alkylborane and an initiator to form a polymer having degradable carbonate or degradable ester linkages incorporated into the polymer backbone polyethylene oxide.

2. The method of claim 1, wherein the degradable polyether is formed under metal-free conditions.

3. The method of any one of claims 1-2, wherein the ethylene oxide monomer is selected from the group consisting of:

4. The method of any one of claims 1-3, wherein the cyclic ester is selected from the group consisting of lactide, trimethylene carbonate, glycolide, beta-butyrolactone , δ-valerolactone, γ-butyrolactone, γ-valerolactone, 4-methyldihydro-2(3H)-furanone, α-methyl-γ-butyrolactone, ε-caprolactone , 1,3-dioxolane-2-one, propylene carbonate, 4-methyl-1,3-dioxan-2-one, 1,3-doxepin-2-one, or 5 -C _1-4alkoxy -1,3-dioxan-2-one.

5. The method according to any one of claims 1 to 4, wherein the alkylborane is selected from the group consisting of triethylborane, triphenylborane, tributylborane, trimethylborane, Triisobutylborane, and combinations thereof.

6. The method according to any one of claims 1 to 5, wherein the initiator has a compound selected from the group consisting of: {Y ⁺ , RO ⁻ }, {Y ⁺ , RCOO ⁻ }, {X ⁺ , N ₃ ⁻ } and the chemical formula of {X ⁺ ,Cl ^- };

wherein Y ⁺ is selected from K ⁺ , t-BuP ₄ ⁺ and t-BuP ₂ ⁺ ;

wherein X ⁺ is selected from NBu ₄ ⁺ , PBu ₄ ⁺ , NOct ₄ ⁺ and PPN ⁺ ;

where RO ^- is selected from

CH ₃ O(CH ₂ ) ₂ O(CH ₂ ) ₂ O ^- and H ₂ C=CHCH ₂ O ^- ;

where RCOO ^- is an aliphatic carbonate or an aromatic carbonate.

7. The degradable polyether formed by the method of any one of claims 1-5, the degradable polyether comprising about 10% or less degradable incorporated into the polyethylene oxide backbone Ester linkages and/or degradable carbonate linkages.

8. The degradable polyether according to any one of claims 1 to 6, the degradable polyether comprising a degradable ester bond or a degradable carbonate bond incorporated into a polyethylene oxide backbone, wherein Each degradable ester bond and each degradable carbonate bond include no more than 10 adjacent ester units or carbonate units, respectively.

9. A modified biomolecule comprising a bioactive molecule associated with the degradable polyether of any one of claims 1-8.

10. The copolymer of claim 9, wherein the biologically active molecule is selected from the group consisting of proteins, peptides, enzymes, pharmaceutical chemicals or organic moieties, and combinations thereof.

11. A method of forming a degradable star polyether comprising:

contacting a diepoxide monomer with carbon dioxide or a cyclic ester in the presence of an initiator and a first amount of alkylborane to form a multifunctional core having degradable carbonate linkages or degradable ester linkages; and

The multifunctional core is contacted with ethylene oxide monomer in the presence of a second amount of alkylborane to form arms of the polyether attached to the multifunctional core.

12. The method of claim 11, wherein the degradable star polyether is formed under metal-free conditions.

13. The method of any one of claims 11-12, wherein each epoxy ring in the diepoxide monomer is ring-opened and copolymerized with carbon dioxide or a cyclic ester.

14. The method of any one of claims 11-13, wherein at least one epoxy ring in the diepoxide monomer is copolymerized with carbon dioxide to form a degradable carbonate bond.

15. The method of any one of claims 11-14, wherein at least one epoxy ring in the diepoxide monomer is copolymerized with a cyclic ester to form a degradable ester bond.

16. The method of any one of claims 11-15, wherein the diepoxide monomer is selected from the group consisting of: vinylcyclohexene dioxide; butadiene dioxide; polyoxyethylene (ethylene glycol diglycidyl); 1,2,3,4-diepoxybutane; 1,2,7,8-diepoxyoctane; 1,2,5,6-diepoxy cyclooctane; dicyclopentadiene diepoxide; poly(ethylene glycol diglycidyl); or compounds such as 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, cyclic Hexane-1,4-diol, cyclohexane-1,1-dimethanol, cyclohexane-1,2-dimethanol, cyclohexane-1,3-dimethanol, cyclohexane-1,4 - Diglycidyl ethers of dimethanol, diethylene glycol, hydroquinone, resorcinol, 4,4-isopropylidene bisphenol or naphthalenediol.

17. The method of any one of claims 11-16, wherein the molar ratio of diepoxide monomer to initiator is not greater than about 10.

18. The degradable star polyether formed according to any one of claims 11 to 17, the degradable star polyether comprising polyether arms attached to a multifunctional polycarbonate core.

19. The degradable star-shaped polyether according to any one of claims 11 to 18, the degradable star-shaped polyether comprising a multifunctional core having at least 80% degradable carbonate or ester linkages.

20. The degradable star polyether of any one of claims 11 to 19, wherein the polyether arms have a number average molecular weight of about 4 kg/mol or greater.